Host genetic variants, Epstein-Barr virus subtypes, and the risk of nasopharyngeal carcinoma: Assessment of interaction and mediation.

Epstein-Barr virus (EBV) and human leukocyte antigen (HLA) polymorphisms are well-known risk factors for nasopharyngeal carcinoma (NPC). However, the combined effects between HLA and EBV on the risk of NPC are unknown. We applied a causal inference framework to disentangle interaction and mediation effects between two host HLA SNPs, rs2860580 and rs2894207, and EBV variant 163364 with a population-based case-control study in NPC-endemic southern China. We discovered the strong interaction effects between the high-risk EBV subtype and both HLA SNPs on NPC risk (rs2860580, relative excess risk due to interaction [RERI] = 4.08, 95% confidence interval [CI] = 2.03-6.14; rs2894207, RERI = 3.37, 95% CI = 1.59-5.15), accounting for the majority of genetic risk effects. These results indicate that HLA genes and the high-risk EBV have joint effects on NPC risk. Prevention strategies targeting the high-risk EBV subtype would largely reduce NPC risk associated with EBV and host genetic susceptibility.

Increasing ratio of opportunistic infections associated with sunshine exposure and economic level burdening Chinese inflammatory bowel disease hospitalized patients: the first nationwide survey from 2014 to 2019.

BACKGROUND: The rising prevalence of opportunistic infections (OIs) in inflammatory bowel disease (IBD) in conjunction with the use of biologics/immunosuppressive agents has garnered attention. However, there is a dearth of research on OIs in Mainland China. This study seeks to evaluate the national ratio trend of OIs in IBD and elucidate the influence of economic and climate factors on IBD patients with OIs and their outcomes. METHODS: The nationwide data was obtained from the Inpatient medical record home page via the Health Statistics and Information Reporting System (HSRS). Patients diagnosed with IBD were enlisted for participation, and their demographic and clinical information, encompassing infection type, surgical procedures, and expenses, were gathered. The National Bureau of Statistics provided data on monthly sunshine exposure hours and yearly Gross Domestic Product (GDP). RESULTS: Findings indicate that between 2014 and 2019, a total of 381,752 patients with IBD were admitted to hospitals, with 364,249 patients lacking OIs and 17,503 patients presenting with OIs. The annual proportion of OIs exhibited an upward trend, rising from 3.54% in 2014 to 4.81% in 2019. There was a significant correlation observed between individuals who identified as male, those who visited hospitals in southern regions, or those originating from areas with lower GDP or shorter sunshine exposure hours, and a higher incidence of OIs. Among patients diagnosed with either Crohn's disease (CD) or ulcerative colitis (UC), Clostridium difficile was found to be the most prevalent infection, followed by Epstein-Barr virus and cytomegalovirus. Furthermore, the occurrence of OIs was found to be associated with an increased rate of surgical interventions in UC patients. CONCLUSIONS: The rising prevalence of OIs among hospitalized patients with IBD necessitates heightened attention towards mitigating associated risk factors, particularly among IBD patients residing in less developed regions or experiencing limited exposure to sunlight. This approach aims to minimize hospital stays and associated costs.

Prevalence, management, and new treatment modalities of EBV-DNA-emia and EBV-PTLD after allo-HCT: survey of Infectious Diseases Working Party EBMT.

The aim of this study was to determine the current approach of EBV-driven post-transplant complications in context of monitoring, diagnosis, prevalence and treatment in EBMT transplant centers. Routine serology testing in patient and donor before HCT is performed in 95.5% centers. Pretransplant EBV-DNA is routinely tested in all patients in 32.7% centers. Monitoring for EBV infection is feasible in 98.2% centers: including 66.7% centers using standardized PCR. Post-HCT regular monitoring is performed in all patients in 80.5% centers. Anti-EBV prophylaxis with rituximab is used in 12.4% centers. Frequency of csEBV-DNA-emia was 7.4% (adults: 6.2%, children: 12.6%). The PCR threshold used to start preemptive treatment was differentiated among centers. Frequency of EBV-PTLD was 1.6% (adults: 1.3%; children: 3.5%). First-line therapy of EBV-driven complications was rituximab and reduction of immunosuppressive therapy. The rate of failure of first-line preemptive treatment was 12.0%. EBV-specific viral-specific T-lymphocytes were available in 46.0% centers. A number of new experimental therapies were given in 28 patients with resistant/refractory PTLD. In conclusion, the prevalence of EBV-DNA-emia and EBV-PTLD over the period 2020-2021 decreased in comparison to historical data. New trends (routine pretransplant screening for EBV-DNA, wider access to VST, new experimental therapies) are being observed in management of EBV infection after allo-HCT.

Assessment of Bone Marrow Involvement in Extranodal NK/T-Cell Lymphoma: Positron Emission Tomography versus Bone Marrow Biopsy, and the Significance of Minimal Involvement by EBV+ Cells (KROG 18-09).

PURPOSE: This study aims to investigate the diagnostic significance of positron emission tomography/computed tomography (PET/CT) in assessing bone marrow (BM) involvement through a comparison of PET/CT findings with BM biopsy in extranodal natural killer/T-cell lymphoma. MATERIALS AND METHODS: The medical records of 193 patients were retrospectively reviewed. Patients were categorized as having early-stage (PET-ES) or advanced-stage (PET-AS) disease based on PET/CT results. The BM involvement was classified into three groups according to BM biopsy: gross BM involvement, minimal BM involvement (defined as the presence of a limited number of Epstein-Barr virus-positive cells in BM), and no involvement. Calculations of the accuracy of PET/CT in detecting BM involvement and analysis of the clinical outcomes (progression-free survival [PFS] and overall survival [OS]) according to the BM biopsy status were performed. RESULTS: PET/CT exhibited a sensitivity of 64.7% and a specificity of 96.0% in detecting gross BM involvement. For detecting any (both gross and minimal) BM involvement, the sensitivity was 30.4%, while the specificity was 99.0%. Only one patient (0.7%) demonstrated gross BM involvement among the PET-ES group. Survival outcomes of the PET-ES group with minimal BM involvement (3-year PFS, 55.6%; OS, 77.0%) were closer to those of the PET-ES group with no BM involvement (3-year PFS, 62.2%; OS, 80.6%) than to those of the PET-AS group (3-year PFS, 20.1%; OS, 29.9%). CONCLUSION: PET/CT exhibits high specificity, but moderate and low sensitivity in detecting gross and minimal BM involvement, respectively. The clinical significance of minimal BM involvement for patients in the PET-ES group may be limited.

Assessment of mimicking by EBV-CMV immunoglobulin M of anti-HLA antibodies.

OBJECTIVE: We aimed to show the cross-reactivity that may occur between immunoglobulin (Ig) M antibodies that form against Cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) and human leukocyte antigens (HLA). METHODS: Complement-dependent cytotoxicity (CDC) cross-reactivity between serum samples of 57 patients with IgM positive CMV and/or EBV infections and T and B cells from 15 healthy donors were evaluated. Dithiothreitol was used to distinguish cross-reactivity caused by IgM antibodies from IgG. RESULTS: The cross-reactivity ratio between pathogenic IgM antibodies with T cell of the 12th donor, and B cell of the 3rd, 4th, and 8th donors was significantly higher (p = 0.011, <0.001, <0.001 and 0.013, respectively). The ratio of B cell CDC cross-reactivity of all donors (26.4%) was higher than the ratio of T cell CDC cross-reactivity (5.2%) (p < 0.001). The ratio of T cell CDC cross-reactivity of sera containing both anti-CMV IgM and anti-EBV IgM antibodies was significantly higher than those of sera containing only anti-CMV IgM or only anti-EBV IgM antibodies (p = 0.002 and p < 0.001, respectively). There was no difference between B cell CDC cross-reactivity rates according to the presence of anti-CMV and/or anti-EBV IgM antibodies. CONCLUSION: Cross-reactivity may occur between anti-CMV and anti-EBV IgM antibodies with HLA molecules. Thus, in graft recipients, pathogenic IgMs can also act as de novo anti-HLA antibodies and aggravate the rejection process.

Possible Concomitant Aggressive NK Cell Leukemia and EBV-positive T-cell lymphoma; Using the online beta version of WHO-HAEM5 and videoconferencing software to make diagnoses accessible in an emerging economy.

BACKGROUND: Using the World Health Organization Classification 5th edition (beta version online; WHO-HAEM5bv) in emerging economies is key to global healthcare equity. Although there may be ongoing updates, hesitancy in accepting and reporting these diagnoses in publication conflicts with the WHO's commitment to global accessibility. Aggressive NK cell leukemia (ANKL) and systemic EBV-positive T-cell lymphoma of childhood (SEBVTCL) with CD4-positive immunophenotype are both rare entities, are most described in Asians and East Asians, are associated with prior systemic chronic active EBV disease (CAEBV), and presentation with Hemophagocytic Lymphohistiocytosis (HLH). Recognizing and diagnosing any one of these entities requires not only training and experience in hematopathology, but good cooperation between clinical physicians and all areas of the laboratory. We describe a 30-year-old woman who presented to a Vietnam hospital and was rapidly diagnosed with ANKL, SEBVTCL, and HLH using WHO-HAEM5bv essential criteria, aided by expert consultation from a United States (US) board certified hematopathologist in real-time using video conferencing software. METHODS: Zoom™ videoconferencing software; Immunohistochemistry; flow cytometric immunophenotyping; polymerase chain reaction (PCR), Next Generation Sequencing (NGS). RESULTS: At the time of hospital admission, automated complete blood count (CBC) with differential count showed slight anemia, slight lymphocytosis, and moderate thrombocytopenia. HIV serology was negative. Whole blood PCR for EBV was positive showing 98,000 copies/ml. A lymph node biopsy revealed histology and immunohistochemistry consistent with the online beta version WHO-HAEM5 classification of SEBVTCL arising in CAEBV. Blood and bone marrow studies performed for staging revealed no histologic or immunohistochemical evidence of T-cell lymphoma in the bone marrow core, however, atypical blood smear lymphocyte morphology and blood immunophenotyping by flow cytometry were consistent with WHO-HAEM5 classification of ANKL. NGS revealed no evidence of genetic variant(s) associated with HLH in Vietnam. All laboratory studies were performed at Blood Transfusion Hematology Hospital (BTHH) in Ho Chi Minh City Vietnam. CONCLUSION: Although Vietnam, an emerging economy, currently lacks the laboratory infrastructure to more rigorously confirm a rare synchronous presentation of two distinct EBV-driven T/NK cell neoplasms, these two concomitant diagnoses were made using only laboratory techniques available in Vietnam with the help of WHO-HAEM5bv and real-time video consultation by a US hematopathologist.

Perceived income inadequacy is associated with Epstein-Barr Virus latency and mental health outcomes in informal caregivers who are also employed in the healthcare industry.

Finances are a prevalent source of stress. In a sample of 799 nursing home workers measured multiple times over 18 months, we found that higher perceived income inadequacy, the perception that one's expenses exceeds one's incomes, was associated with poorer self-reported mental health indicators and Epstein-Barr Virus antibody titers (a marker of cell-mediated immune function). Perceived income inadequacy predicted outcomes over and above the role of other socioeconomic status variables (objective household income and education). Mental health variables were not related to Epstein-Barr Virus antibody titers. Additionally, we found an interaction between perceived income inadequacy and informal caregiver status on our mental health outcomes; informal caregivers with higher perceived income inadequacy had poorer mental health than non-caregivers with the same perceived income inadequacy. Our findings may add nuance to the reserve capacity model, which states that those at lower socioeconomic levels are at higher risk of adverse health outcomes partly because they have fewer resources to address demands and strain. Perceived income inadequacy may significantly predict mental and physical well-being beyond other socioeconomic status variables, especially among lower-income employees. Caregiving stress and perceived income inadequacy may have synergistic effects on mental health.

Diagnosis of Epstein-Barr and cytomegalovirus infections using decision trees: an effective way to avoid antibiotic overuse in paediatric tonsillopharyngitis.

BACKGROUND: The incidence of tonsillopharyngitis is especially prevalent in children. Despite the fact that viruses cause the majority of infections, antibiotics are frequently used as a treatment, contrary to international guidelines. This is not only an inappropriate method of treatment for viral infections, but it also significantly contributes to the emergence of antibiotic-resistant strains. In this study, EBV and CMV-related tonsillopharyngitis were distinguished from other pathogens by using machine learning techniques to construct a classification tree based on clinical characteristics. MATERIALS AND METHODS: In 2016 and 2017, we assessed information regarding 242 children with tonsillopharyngitis. Patients were categorized according to whether acute cytomegalovirus or Epstein-Barr virus infections were confirmed (n = 91) or not (n = 151). Based on symptoms and blood test parameters, we constructed decision trees to discriminate the two groups. The classification efficiency of the model was characterized by its sensitivity, specificity, positive predictive value, and negative predictive value. Fisher's exact and Welch's tests were used to perform univariable statistical analyses. RESULTS: The best decision tree distinguished EBV/CMV infection from non-EBV/CMV group with 83.33% positive predictive value, 88.90% sensitivity and 90.30% specificity. GPT (U/l) was found to be the most discriminatory variable (p < 0.0001). Using the model, unnecessary antibiotic treatment could be reduced by 66.66% (p = 0.0002). DISCUSSION: Our classification model can be used as a diagnostic decision support tool to distinguish EBC/CMV infection from non EBV/CMV tonsillopharyngitis, thereby significantly reducing the overuse of antibiotics. It is hoped that the model may become a tool worth considering in routine clinical practice and may be developed to differentiate between viral and bacterial infections.

A cost-effective strategy for selection of third-party donors for a virus-specific T-cell bank for an Asian patient population.

BACKGROUND AIMS: Third party virus-specific T cells (VST) has shown efficacy for opportunistic virus infection which do not have effective treatment or are drug-refractory. We describe our preparatory work in setting up a third-party VST bank for a multi-ethnic Asian population. METHODS: Discarded white cells from regular blood bank plateletpheresis donors with known locally prevalent HLA antigens were cultured in small scale to generate VST against Adenovirus, BK virus, Cytomegalovirus, Epstein-Barr virus, and Human Herpes Virus 6. Multi-virus specific T cells (multi-VST) were also generated against all 5 viruses in single cultures. A strategy of allelic typing for donors with good and broad-spectrum cytotoxicity together with consideration on HLA restriction for the virus epitope was used to select combinations of VST lines for a hypothetical third party VST bank. The breadth of coverage based on these selection criteria was validated using our database of 100 post haematopoietic stem cell transplant patients. RESULTS: We show that 50%, 42%, 56%, 56% and 42% of single VST cultures demonstrated specific cytotoxicity against AdV, BKV, CMV, EBV and HHV6 respectively. Twenty four of the 36 multi-VST lines showed activity against at least 2 of the 5 viruses studied. A carefully selected combination of just 6 VST lines can offer VST with at least 1 allelic match to 99% of potential recipients, while 92% can find 2 allelic matches and 79% can find 3 allelic matches. CONCLUSIONS: This preparatory work confirms that a cost-effective strategy recruiting a small number of pre-characterized donors can generate VST lines with broad coverage for a multi-ethnic Asian patient population, thereby laying the foundation for setting up of a third party VST bank for Asian patients.

Screening costs associated with donor selection for fecal microbiota transplantation for treatment of PD-1 refractory melanoma patients.

The gut microbiome acts as a tumor-extrinsic regulator of responses to immune-checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors. Primary resistance to anti-PD-1 ICI can be reversed via responder-derived fecal microbiota transplant (FMT) in patients with refractory melanoma. Efforts to create stool banks for FMT have proved difficult. Therefore, we aimed to establish a novel donor-screening program to generate responder-derived FMT for use in PD-1 refractory melanoma. Candidate PD-1 responder donors and PD-1 refractory recipients were recruited via clinic-based encounters at the University of Pittsburgh Medical Center hospitals. Eligible donors and recipients underwent physician assessment and screening of serum, stool and nasopharynx for transmissible agents, which included SARS-CoV-2 modification. The cost of donor and recipient screening was calculated. Initially, 29 donors were screened with 14 eligible donors identified after exclusion; of the 14 donors, eight were utilized in clinical trials. The overall efficiency of screening was 48%. Seroprevalence rates for cytomegalovirus, Epstein-Barr virus, HSV-2, HHV-6, HTLV-1, HTLV-2, and syphilis were similar to published statistics from healthy blood donors in the USA. Donor stool studies indicated a 3.6% incidence of E. histolytica and norovirus, 3.7% incidence of giardia and 7.1% incidence of C. difficile. A single donor tested positive for SARS-CoV-2 in stool only. The cost for finding a single eligible donor was $2260.24 (pre-COVID) and $2,460.24 (post-COVID). The observed screening efficiency suggests that a well-resourced screening program can generate sufficient responder-derived donor material for clinical trial purposes. Eliminating testing for low-prevalence organisms may improve cost-effectiveness.

Assessment of the cytolytic potential of a multivirus-targeted T cell therapy using a vital dye-based, flow cytometric assay.

Reliable and sensitive characterization assays are important determinants of the successful clinical translation of immunotherapies. For the assessment of cytolytic potential, the chromium 51 (51Cr) release assay has long been considered the gold standard for testing effector cells. However, attaining the approvals to access and use radioactive isotopes is becoming increasingly complex, while technical aspects [i.e. sensitivity, short (4-6 hours) assay duration] may lead to suboptimal performance. This has been the case with our ex vivo expanded, polyclonal (CD4+ and CD8+) multivirus-specific T cell (multiVST) lines, which recognize 5 difficult-to-treat viruses [Adenovirus (AdV), BK virus (BKV), cytomegalovirus (CMV), Epstein Barr virus (EBV), and human herpes virus 6 (HHV6)] and when administered to allogeneic hematopoietic stem cell (HCT) or solid organ transplant (SOT) recipients have been associated with clinical benefit. However, despite mediating potent antiviral effects in vivo, capturing in vitro cytotoxic potential has proven difficult in a traditional 51Cr release assay. Now, in addition to cytotoxicity surrogates, including CD107a and Granzyme B, we report on an alternative, vital dye -based, flow cytometric platform in which superior sensitivity and prolonged effector:target co-culture duration enabled the reliable detection of both CD4- and CD8-mediated in vitro cytolytic activity against viral targets without non-specific effects.

Combined assessment of Epstein-Barr virus viral capsid antigen and Epstein-Barr virus nuclear antigen-1 serology for post-transplant lymphoproliferative disorder risk stratification in adult solid organ transplant recipients.

BACKGROUND: Epstein-Barr virus (EBV) seronegative solid organ transplant recipients (SOTRs) are at increased risk for post-transplant lymphoproliferative disorder (PTLD). Assays for EBV serostatus assess antibody to both EBV viral capsid antigen (VCA) and Epstein-Barr nuclear antigen-1 (EBNA-1), but PTLD risk among SOT recipients with discordant VCA and EBNA-1 results is unknown. METHODS: We performed a retrospective, single-center cohort study to determine the risk of PTLD among adult (≥ 18 years) SOTRs with discordant pre-transplant VCA and EBNA-1 IgG compared to that of SOTRs with concordantly negative or concordantly positive serology using univariable and multivariable Cox-proportional hazards models. RESULTS: Of 4106 SOTRs, the number (%) who were concordantly positive, concordantly negative, and discordant was 3787 (92.2%), 149 (3.6%), and 170 (4.2%), respectively. The adjusted hazard of PTLD was significantly higher among discordant SOTRs compared to concordantly positive SOTRs (aHR 2.6, 95% CI 1.04-6.6, p =.04) and lower compared to concordantly negative SOTRs (aHR 0.27, 95% CI 0.10-0.76, p <.001). The adjusted hazard of EBV+ PTLD among those with discordant serology was also significantly higher compared to the concordantly positive cohort (aHR 3.53, 95% CI 1.04-12.0, p =.04) and significantly lower compared to the concordantly negative cohort (aHR 0.23, 95% CI 0.06-0.82, p =.02). CONCLUSIONS: Risk of PTLD among SOTRs with discordant VCA and EBNA-1 may be intermediate between those with concordantly positive and negative serology. If confirmed in future studies, revision of national EBV serology reporting to include both VCA and EBNA results may be needed to optimize PTLD risk stratification.

Flow cytometry assessment of reactive T-cells distinguishes classic Hodgkin lymphoma from benign lymphadenopathy in children.

BACKGROUND: Detection of classic Hodgkin lymphoma (cHL) neoplastic cells using flow cytometric immunophenotyping (FCI) remains limited. We hypothesized that characterization of the reactive infiltrates could assist in diagnosing cHL in children. METHODS: FCI using four-color staining approaches was performed on 156 lymph node specimens with the following histopathologic diagnoses: cHL (25 cases), reactive lymphoid hyperplasia (RLH, 44 cases), and non-Hodgkin lymphoma (87 cases). RESULTS: The overall concordance of FCI data with the histopathologic results of these cases was 81.4%. A reactive expansion of T-cells with increased expression of CD45RO was present in the reactive infiltrate of cHL (CD45RO/CD3, 67.5%) and Epstein-Barr virus (EBV) infected RLH (62.7%) but not in EBV-negative RLH (28.0%). The mean fluorescence intensity (MFI) of CD7 was higher for cHL and differed significantly from EBV-positive RLH (138.5 vs. 63.8). A proposed diagnostic algorithm markedly elevated the overall concordance rate from 81.4% to 97.4%. CONCLUSIONS: Immunophenotyping the reactive infiltrate of lymphoid tissue using flow cytometry is a reliable supplement to histopathology for the rapid diagnosis of pediatric cHL.

Epidemiological characteristics and disease burden of infectious mononucleosis in hospitalized children in China: A nationwide retrospective study.

Epstein-Barr virus (EBV) is very common, with the infection rate in adults over 90% worldwide. Infectious mononucleosis (IM) is caused by primary infection with EBV. Most IM patients are generally considered to have a favorable prognosis, but a few patients will also develop complications. Children with severe symptoms will require hospitalization. However, the disease burden of children hospitalized with IM in China has been rarely described. In this study, we included the Face sheets of discharge medical records from 27 member children's hospitals of Futang Research Center of Pediatric Development from Jan 1st, 2016 to Dec 31st, 2020, and medical information such as gender, age, region, time of admission, length of stay and expenditure were extracted. There were 24,120 IM cases, which accounted for 0.42% (24,120/5,693,262) of all hospitalized cases during this period. The ratio of male to female was 1.48:1. Hospitalization for IM in the 4-6 â€‹years age group was the highest among inpatients of all age groups. Case numbers increased year by year between 2016 and 2020, and the monthly hospitalization was generally high from Jul to Sep but reduced from Jan to Feb per year. Bronchitis/pneumonia and hepatic dysfunction were two common complications in hospitalized IM patients. The median length of stay was 8 days, and the median cost of hospitalization was 970.59 US dollars. This study will help understand the epidemiological characteristics and disease burden of hospitalized children with IM in China.

Clinical and Economic Burden of Multiple Double-Stranded DNA Viral Infections after Allogeneic Hematopoietic Cell Transplantation.

Conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT) are immunosuppressive and increase the risk for reactivation of and infection with double-stranded DNA (dsDNA) viruses, which contribute to morbidity and mortality after allo-HCT. This retrospective observational study evaluated the association of dsDNA viral infections with clinical outcomes, health resource utilization (HRU), and health care reimbursement after allo-HCT. Patients who underwent allo-HCT between 2012 and 2017 were identified from a US open-source claims database (Decision Resource Group Real-World Evidence Data Repository; n = 13,363) and categorized according to the presence or absence of dsDNA viral infection, defined as having ≥1 diagnosis code for cytomegalovirus (CMV), adenovirus (AdV), human herpesvirus 6 (HHV-6), or BK virus (BKV)/Epstein-Barr virus (EBV)/John Cunningham virus (JCV) (grouped together given a lack of specific diagnoses codes) within 1 year after allo-HCT. Only first allo-HCT data were used in patients who underwent multiple procedures. Study outcomes included clinical outcomes (eg, time to all-cause mortality, new diagnosis of renal impairment), HRU (hospital and intensive care unit length of stay [LOS], readmission rates), and health care reimbursement (total, inpatient, and outpatient costs as reported reimbursements from insurance claims). For all outcomes, patients were stratified by the presence/absence of any dsDNA viral infection and number (none, 1, 2, or ≥3) and type(s) of infection. The effect of graft-versus-host disease (GVHD) was assessed as well. Twenty-nine percent of patients were diagnosed with CMV, 13% with BKV/EBV/JCV, 5% with AdV, and 4% with HHV-6 in the year following their first allo-HCT. A single dsDNA viral infection was documented in 30% of individuals, 2 in 8%, and ≥3 in 2%. Patients with no viral infections had an overall hospital LOS (index hospitalization plus readmissions) of 41.3 days and a total health care reimbursement of $266,345. These numbers increased for every additional viral infection, regardless of the presence or absence of GVHD; the overall hospital LOS was 61.4 days and total healthcare reimbursement was $431,614 in patients with 1 viral infection, 77.0 days and $639,097 in patients with 2 viral infections, and 103.3 days and $964,378 in patients with ≥3 viral infections. An increase in the number of dsDNA viral infections was associated with a significantly higher adjusted hazard of all-cause mortality (1 versus 0 dsDNA viral infections: hazard ratio [HR], 1.5; [95% confidence interval (CI), 1.3 to 1.6]; 2 versus 0: HR, 2.0 [95% CI, 1.7 to 2.3]; ≥3 versus 0: HR, 2.4 [95% CI, 1.8 to 3.3]) and a significantly higher incidence of new diagnosis of renal impairment, regardless of the presence of GVHD (35% of patients with ≥3 infections, 31% of patients with 2 infections, 26% of patients with 1 infection, and 19% of patients with no infection). These results indicate that more directed prevention and treatment strategies for dsDNA viral infections could substantially improve clinical outcomes and reduce HRU.

Cost-Effectiveness analysis of combining plasma Epstein-Barr virus DNA testing and different surveillance imaging modalities for nasopharyngeal carcinoma patients in first remission.

BACKGROUND: To evaluate the cost-effectiveness of stage-based post-radiotherapy (PRT) nasopharyngeal carcinoma (NPC) surveillance strategies. METHODS: Four post-radiotherapy surveillance strategies were established by a Markov model based on data from 1664 patients: 1) clinical follow-up (CFP) with biannual Epstein-Barr virus (EBV) DNA (EBV DNA strategy); 2) CFP with biannual EBV DNA, annual head and neck magnetic resonance imaging (HNMRI), chest X-ray, abdominal ultrasonography, bone scan (only for the first two years) for five years (MCWU strategy); 3) CFP with biannual EBV DNA, annual HNMRI, chest, abdomen, pelvic computerized tomography (CT) and bone scan for the first two years, followed by annual MCWU strategy (without bone scans) for the last three years (CT strategy); 4) CFP with biannual EBV DNA, annual whole-body positron emission/computerized tomography (PET/CT) for the first two years and biannual EBV DNA for the last three years (PET/CT strategy). RESULTS: Compared with the EBV DNA strategy, the MCWU, CT, and PET/CT strategies gained 0.017, 0.047, and 0.082 quality-adjusted life years (QALY) for stage I-II patients. For stage III and IVa patients, the PET/CT strategy had a favorable incremental effectiveness (ICERs) of 0.277 and 0.385 QALY, respectively. The ICERs for the MCWU, CT, and PET/CT strategies were $74,037, $34,882, and $34,696 for stage III and $62,364, $27,981, and $28,340 for stage IVa, respectively. CONCLUSION: EBV DNA strategy was cost-effective for the long-term surveillance of stage I-II NPC patients with CR. PET/CT strategy was recommeded for patients having IVa NPC. As for stage III NPC, PET/CT strategy was still acceptable with the development of economy in China.

Assessment of the Serologic Status in Epstein-Barr Virus in Patients Qualified for Lung Transplantation in the First Half of 2021.

BACKGROUND: The aim of the study was to assessment serologic status of Epstein-Barr virus (EBV) infections in patients qualificated for lung transplantation in the first half of 2021. METHODS: The study included 72 patients qualified for lung transplantation from January to June 2021. The youngest patient was aged 14 years and the oldest was aged 65 years. The study group consisted of 36 women and 36 men. In the serum of patients, a multi-parameter, comprehensive diagnosis of EBV infections was performed using the IIFT BIOCHIP EBV sequence tests. This test is based on a combination of several substrates, enabling the simultaneous evaluation of antibodies against capsid antigens (anti-CA antibodies), both in the IgG and IgM class, early antigens (anti-EA), nuclear antigens and the assessment of the avidity of anti-CA antibodies. The analysis of all diagnostically significant antibodies specific for EBV infections, including the avidity of anti-CA antibodies, increases the diagnostic accuracy in differentiating active and past infection with EBV. RESULTS: In the studied group it was shown that 58 had past EBV infection (80.6%). Twelve patients (16.6%) have anti-EA antibodies, which indicate that the virus is reactivated. Only 2 patients (2.8%) had no antibodies to EBV. CONCLUSIONS: Comprehensive assessment of antibodies against various EBV antigens in patients qualified for lung transplantation is important in the management and further diagnosis of this infection, especially after transplantation, due to the risk of developing post-transplant lymphoproliferative disease.

BRCA1 Variant Assessment Using a Simple Analytic Assay.

BACKGROUND: We previously developed a biological assay to accurately predict BRCA1 (BRCA1 DNA repair associated) mutation status, based on gene expression profiles of Epstein-Barr virus-transformed lymphoblastoid cell lines. The original work was done using whole genome expression microarrays, and nearest shrunken centroids analysis. While these approaches are appropriate for model building, they are difficult to implement clinically, where more targeted testing and analysis are required for time and cost savings. METHODS: Here, we describe adaptation of the original predictor to use the NanoString nCounter platform for testing, with analysis based on the k-top scoring pairs (k-TSP) method. RESULTS: Assessing gene expression using the nCounter platform on a set of lymphoblastoid cell lines yielded 93.8% agreement with the microarray-derived data, and 87.5% overall correct classification of BRCA1 carriers and controls. Using the original gene expression microarray data used to develop our predictor with nearest shrunken centroids, we rebuilt a classifier based on the k-TSP method. This classifier relies on the relative expression of 10 pairs of genes, compared to the original 43 identified by nearest shrunken centroids (NSC), and was 96.2% concordant with the original training set prediction, with a 94.3% overall correct classification of BRCA1 carriers and controls. CONCLUSIONS: The k-TSP classifier was shown to accurately predict BRCA1 status using data generated on the nCounter platform and is feasible for initiating a clinical validation.

Selectively recommend 18F-FDG PET/CT for patients with de novo nasopharyngeal carcinoma in endemic areas.

INTRODUCTION: To identify the subset of patients with de novo nasopharyngeal carcinoma (NPC) for whom [18F] fluorodeoxyglucose positron emission tomography and computed tomography (18F-FDG PET/CT) should be recommended, and to determine whether PET/CT is a cost-effective decision for precise M staging in endemic areas. MATERIALS AND METHODS: Retrospective analysis of data of 4469 patients diagnosed with de novo NPC between January 2014 and December 2019. The detection rate of distant metastasis was compared between different groups. Univariate and multiple logistic regression analysis was applied to identify the risk factors for distant metastasis. The cost-effectiveness of the diagnostic strategies was assessed. RESULTS: The detection rate of distant metastasis in the whole cohort was 5.46%. In multivariate analysis, male sex, T3-4 stage, N2-3 stage, and high plasma Epstein-Barr virus (EBV) DNA (≥ 14,650 copies/mL) were risk factors for distant metastases. NPC patients with T3-4 stage combined with N2-3 stage, high EBV DNA combined with male sex, or N2-3 stage combined with high EBV DNA were defined as recommended group with relatively higher tendency for metastasis. Distant metastasis incidence in recommended group and unrecommended group were 10.25% and 1.75%, respectively (P < 0.001). In the recommended group, PET/CT significantly improved the detection rate of distant metastasis (13.25% vs 9.02%, P = 0.005). Cost-effectiveness analysis revealed that additional cost for every one percent increase in distant metastasis detection rate was $22,785.58 in the recommended group (< Willingness-to-pay (WTP) threshold of $32,700.00) and $310,912.90 in the unrecommended group. CONCLUSIONS: In patients with de novo NPC, the tendency for metastasis can be predicted based on clinical parameters. 18F-FDG PET/CT should be selectively recommended for the subset of patients with a relatively higher tendency for metastasis.